Penn vet study shows how solid tumors resist immunotherapy
Adapted Media Release
Wed 15 Feb 2017
Immunotherapies have revolutionized cancer treatment, offering hope to those whose malignancies have stubbornly survived other existing treatments. Yet solid tumor cancers are often resistant to these approaches.
New findings from a University of Pennsylvania-led team untangle one of the ways tumors evade immune detection and show how immunotherapies can be modified to tackle even these solid tumors.
The focus of the study was the protein type I interferon receptor IFNAR1, which is activated by interferon, a molecule that is known to fight cancers and is itself a treatment for cancer, infections and other conditions. When a tumor forms, the hypoxic environment of its fast-growing mass leads to a reduction in levels of the interferon receptor on T cells. This reduction precipitates the T cells’ demise, thus creating an environment where cancer cells can survive and reproduce unchecked.
“We found that this downregulation of the receptor is required for the generation of immune-privileged niches in the tumor microenvironment,” said Serge Y. Fuchs, a professor of cell biology in Penn’s School of Veterinary Medicine, director of the school’s Mari Lowe Center for Comparative Oncology and senior author on the study. “Accordingly, this decreases the efficacy of immune therapies. So, if we can reverse that, then we’ll probably improve the outcome of treatment.”
Fuchs collaborated on the work with Penn Vet’s Kanstantsin V. Katlinski, Jun Gui, Yuliya V. Katlinskaya, Angelica Ortiz, Riddhita Chakraborty, Sabyasachi Bhattacharya, Christopher J. Carbone, Daniel P. Beiting and Ellen Puré; Priya Chatterji, Anil K. Rustgi and Constantinos Koumenis of Penn’s Perelman School of Medicine; the Medical College of Wisconsin’s Melanie A. Girondo, Amy R. Peck and Hallgeir Rui; and the Medical University of South Carolina’s J. Alan Diehl.
The work appears in the journal Cancer Cell.
Fuchs’ laboratory has long been intrigued by IFNAR1, a receptor that plays an important role in cancers, inflammation, autoimmune diseases and viral infections. Most cellular receptors are subject to a negative feedback loop; when their corresponding extracellular molecule activate the receptor, it triggers a pathway that then leads to that receptor being reduced, presumably to avoid the cell being overloaded with signaling through that pathway.
Yet about a decade ago, Fuchs and colleagues discovered that IFNAR1 is downregulated not only upon activation with interferon but also through another pathway that robs the cells of their ability to recognize interferon.
“And when we found that some of the stimuli that can remove IFNAR1 from the cell surface are similar to those that occur in the tumor microenvironment,” Fuchs said, “we became curious if the loss of the receptor happens in the tumors.”
Solid tumors present a stressful environment. They grow so rapidly that blood-vessel growth can’t keep up, thus cells deep inside tumors are often left wanting for oxygen or nutrients like glucose and amino acids.
At the same time, researchers including study author Koumenis had found that immune-related genes dropped in expression in the deep tumor microenvironment, creating what is referred to as an immune-privileged niche.
In the current work, the research team investigated whether IFNAR1 was involved in this dip in immunity, looking specifically at colorectal cancer, a disease that does not respond well to immunotherapies. Examining tissue samples from people with colorectal cancer, the researchers found dramatic differences in IFNAR1 protein levels between normal and cancerous tissue; the cancer cells showed complete or near-complete loss of the protein. This loss was also associated with poorer outcomes in patients.
The researchers then turned to mice to determine exactly how IFNAR1 loss related to tumor growth. Mice with a form of colorectal cancer had a corresponding decline in IFNAR1 protein, but those bred to have a form of IFNAR1 resistant to degradation had fewer tumors.
The researchers next used a model in which mice received a transplant of tumor cells. While tumors grew on genetically normal mice, mice with the degradation-resistant IFNAR1 either rejected the tumor cells or displayed a delay in tumor growth.
Because T cells are known to be able to fight tumors, the researchers looked at T cell levels in mice with the degradation-resistant form of IFNAR1 compared to the normal mice and found that the latter group had significantly reduced numbers of a number of immune cells, including so-called “killer” T cells, inside the tumors. Further experiments confirmed that the downregulation of IFNAR1 on T cells greatly decreased the cells’ ability to survive in the tumor microenvironment.
This discovery helps explain why immunotherapies based on genetically engineering T cells have low efficacy in solid tumor cancers: they simply can’t survive long enough to have an effect against the cancer cells.
To put their findings into action, the researchers tweaked the typical T cell immunotherapy approach by stabilizing IFNAR1 in the transferred T cells by inactivating or inhibiting the enzymes normally involved in degrading the receptor. This was able to restore levels of the receptor in the cytotoxic T lymphocytes, increasing their numbers inside the tumors, where they had a strong anti-tumorigenic effect.
“Based on that we were able to make a better immunotherapy,” said Fuchs.
He and colleagues are working to develop a model where they could use a drug to stabilize the receptors and are also investigating a way to put a stabilized receptor into a CAR-T cell therapy.
“Technically it’s not very simple, but it should be feasible,” Fuchs said. “And that would be very, very sweet.”
The research was supported by the National Institutes of Health.
Article: Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment, Serge Y. Fuchs et al., Cancer Cell, doi: 10.1016/j.ccell.2017.01.004, published 13 February 2017.
Rate this article
Penn vet study shows how solid tumors resist immunotherapy
Public / Patient
Not yet rated
Source: University of Pennsylvania
Additional source: EurekAlert!, the online, global news service operated by AAAS, the science society
Please use one of the following formats to cite this article in your essay, paper or report:
University of Pennsylvania. “Penn vet study shows how solid tumors resist immunotherapy.” Medical News Today. MediLexicon, Intl., 15 Feb. 2017. Web.
26 Feb. 2017. <http://www.medicalnewstoday.com/releases/315858.php>
University of Pennsylvania. (2017, February 15). “Penn vet study shows how solid tumors resist immunotherapy.” Medical News Today. Retrieved from
Please note: If no author information is provided, the source is cited instead.
Contact our news editors
For any corrections of factual information, or to contact our editorial team, please see our contact page.
Copyright Medical News Today: Excluding email/sharing services explicitly offered on this website, material published on Medical News Today may not be reproduced, or distributed without the prior written permission of Medilexicon International Ltd. Please contact us for further details.
Spotlight on: Cancer / Oncology
- What is Cancer?Learn all about cancer, a condition caused by out-of-control cell growth in specific parts of the body. Find out about the different types of cancer, symptoms, causes and treatments.
Most popular in: Cancer / Oncology
- How are calluses and throat cancer related?
- Scientists inhibit brain tumor cell growth, paving way for new treatment
- Brain Tumor: Types, Symptoms, and Treatment
- Gut bacteria mediate link between diet and colorectal cancer
- Eating 10 portions of fruits and veg daily best for health
- Oxygen-starved cancer cells programmed to evade therapy after spreading
- Cancer: New method tags elusive tumors for targeted therapy
- Breast cancer: Changes in immune cell composition linked to future risk
- Detailed articles about specific areas of medicine, conditions, nutrition, and forms of treatment.Visit now
Or choose a specific subject below.
— Select a subject —
Acoustic Neuroma (Vestibular Schwannoma)
Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Acute Respiratory Distress Syndrome
Addison’s Disease (Primary Adrenal Insufficiency)
Air Embolism (Gas Embolism)
Alcoholic Liver Disease
Altitude Sickness (Acute Mountain Sickness)
AMD / Macular Degeneration
Amyotrophic Lateral Sclerosis (ALS)
Anal Itching (Itchy Bottom)
Androgen Insensitivity Syndrome (AIS)
Anemia (Vitamin Deficiency)
Antiphospholipid Syndrome (Hughes Syndrome)
Atrophic Vaginitis (Vaginal Atrophy)
Baker’s Cyst (Popliteal Cyst)
Bed Sores (Pressure Ulcers)
Binge Eating Disorder
Body Dysmorphic Disorder
Body dysmorphic disorder
Body Odor (B.O.)
Boils, furuncles, carbuncles
Borderline Personality Disorder (BPD)
Brain Abscess (Cerebral Abscess)
Breast Cancer (Male)
Breast Pain (Mastalgia)
Carbon Monoxide Poisoning
Carpal Tunnel Syndrome
Cholecystitis (Gallbladder Inflammation)
Cholestasis Of Pregnancy (Obstetric Cholestasis)
Chronic Fatigue Syndrome (CFS)
Chronic Kidney Failure
Chronic Rhinosinusitis (CRS)
Clostridium Difficile (C. Difficile)
Clubfoot (Talipes Equinovarus)
Complex Regional Pain Syndrome (CRPS)
Congenital Heart Disease (Congenital Heart Defect)
Corns / Calluses
Coronary Heart Disease (Coronary Artery Disease)
Crabs (Pubic Lice)
Creutzfeldt-Jakob disease (CJD)
Cryptorchidism (Undescended Testicle)
Deep Vein Thrombosis
Degenerative Disc Disease
Discoid Eczema (Nummular Dermatitis)
Disorganized Schizophrenia (Hebephrenia)
Double Vision (Diplopia)
Dry Eye Syndrome
Dry Mouth (Xerostomia)
Enuresis – Bedwetting
Epiphora (Watering Eye)
Euthanasia (Assisted Suicide)
Exophthalmos (Bulging Eyes)
Eye Melanoma (Ocular Melanoma)
Febrile Seizures (Convulsions)
Female Genital Mutilation
Flat Feet (Fallen Arches)
Fracture (Broken Bones)
Gastroenteritis / Food Poisoning
Gluten Intolerance / Celiac Disease
Gum Disease (Gingivitis)
Hair Loss / Baldness
Halitosis (Bad Breath)
Hashimoto’s Thyroiditis (Hashimoto’s Disease)
Hearing Impairment (Deafness)
Heart Block (AV Bundle/Bundle Branch Block)
Heat Rash (Prickly Heat)
Heat Stroke (Sunstroke)
Hemroids / Hemorrhoids
High Blood Pressure
Hirsutism (Excessive Hairiness)
HIV / AIDS
Hormone Replacement Therapy (HRT)
Hydrocephalus (Water On The Brain)
Hyperhidrosis (Excessive Sweating)
Hypertension (High Blood Pressure)
Impacted Wisdom Teeth
Influenza / Flu
Irregular Periods (Oligomenorrhea)
Irritable Bowel Syndrome (IBS)
Irritable Hip (Acute Transient Synovitis)
Kidney Infection (Pyelonephritis)
Laryngeal Cancer (Cancer Of The Larynx)
Listeria Infection (Listeriosis)
Mal De Debarquement Syndrome (MdDS)
Metatarsalgia (Stone Bruise)
Morning Sickness (Nausea Gravidarum)
Motion Sickness (Travel Sickness)
Motor Neuron Disease
Munchausen Syndrome By Proxy
Muscular Dystrophy (MD)
Myasthenia Gravis (Goldflam Disease)
Nail Fungal Infection
Narcissistic Personality Disorder
Neuromyelitis Optica (Devic’s Disease)
Nicotine Dependence (Dangers Of Smoking)
Obsessive-Compulsive Disorder (OCD)
Opioid-Induced Constipation (OIC)
Oral Thrush (Babies)
Oral Thrush (Oral Candidiasis)
Osteomyelitis (Bone Infection)
Otitis Externa (Swimmer’s Ear)
Paget’s Disease (Of Bone)
Paget’s Disease (Of Breast)
Painful Intercourse (Dyspareunia)
Pelvic Inflammatory Disease
Peripheral Artery Disease (PAD)
Poison Ivy Rash
Polycystic Ovary Syndrome (PCOS)
Polyuria (Frequent Urination)
Post Traumatic Stress Disorder (PTSD)
Premenstrual dysphoric disorder (PMDD)
Premenstrual Syndrome (PMS)
Primary Sclerosing Cholangitis
Pulmonary Edema (Oedema)
Radiation Sickness (Radiation Poisoning)
Ramsay Hunt Syndrome
REM Behavior Disorder
Repetitive Strain Injury (RSI)
Respiratory Syncytial Virus
Restless Legs Syndrome
Salivary Gland Cancer
Scarlet Fever (Scarlatina)
Seasonal Affective Disorder
Sexual Addiction (Nymphomania)
Short Stature (Dwarfism)
Skin Cancer / Melanoma
Slapped Cheek Syndrome
Social Anxiety Disorder
Spinal Muscular Atrophy
Stomach Cancer (Gastric Cancer)
Strep Throat / Sore Throat
Tachycardia (Fast Heart Beat)
Teeth Grinding (Bruxism)
Tiredness / Fatigue
Tobacco Smoke Toxins
Toxic Shock Syndrome (TSS)
Transient Ischemic Attack
transient ischemic attack
Traumatic Brain Injury (TBI)
Triple X Syndrome
Urinary Tract Infection (UTI)
Valley Fever (Coccidioidomycosis)
Varicose Eczema (Stasis Dermatitis)
Vesicoureteral Reflux (VUR)
Vitamin B12 Deficiency
Vocal Cord Paresis (Paralysis)
Von Willebrand Disease
Vulvar Cancer (Vulval Cancer)
Water On The Knee (Knee Effusion)
Water Retention (Fluid Retention)
West Nile Virus (WNV)
Whooping Cough (Pertussis)
Wilms’ Tumor (Nephroblastoma)
Yeast infection (male)